Can biosimilar products be interchangeable? Pharmaceutical perspective in the implementation of biosimilars in oncology

Abstract

Objective

To evaluate the safety in the interchangeability of biosimilar products approved for cancer treatment from a pharmaceutical perspective.

Methods

A literature review was carried out using the descriptors “Biosimilar”, “Oncology Therapy”, “Interchangeable drugs” and “Biological Products”, in the Sciencedirect, MEDLINE, and CAPLUS databases.

Results

Fifty-one articles were selected, which addressed the importance of establishing standards that prove the efficacy and safety of biosimilars with reference products, as well as the growing interest of the pharmaceutical industry in the development of biosimilars and the impact on costs and changes in the perspective of the treatment of cancer patients.

Conclusions

As they are large and complex molecules, it is impossible to obtain identical copies of their reference products, which generates conflicts and concerns on the part of the pharmaceutical class regarding the safety in the interchangeability of these products, highlighting the importance of pharmacovigilance in this process.

Keywords

Introduction

With the advancement of technology, it was possible to improve and introduce sophisticated techniques that allow an accurate diagnosis of cancer and the detailing of specific tumor markers present in several cancer types. The discovery of tumor markers, as well as the use of immunohistochemistry in the search for overexpressed receptors in cancer cells, allowed the development of drugs with action directed at these overexpressed receptors.^1–3

The idea of targeting the treatment and making it more specific to each tumor seems to be working. The introduction of products developed from biological materials gains space every year, enabling the development of new drugs with reduced toxicity and with therapeutic potentials, many times even superior to commercial drugs, as it allows specific targeting.⁴

Biological products are an important component in cancer treatment, however, the development of biosimilars from reference drugs is a complex and expensive process.⁵ The term biosimilar is defined by the US FDA as a highly similar biological product and without clinically significant differences from a reference product, requiring extensive analysis when the structure and pharmacological function of the reference product and the proposed biosimilar.^4,6–8 Despite the small differences in the inactive components, a similar biological product cannot show clinically significant differences from the reference product.⁹ Table 1 shows some similarities and differences between biosimilar products and their reference products.

Table 1.

Differences and similarities between biosimilar products and their reference products.

Similarities	Differences
Large molecules, with high molecular weight and complex structure.	The chemical structure of biosimilar products is not 100% identical to the reference products.
Produced in living organisms.	Similar activity, but not equivalent.
High sensitivity to physical factors.	Reference products may have some different therapeutic indications of the biosimilar, although some regulatory agencies allow the extrapolation of indications.
Target-specific toxicity.	May show slight differences in the pharmacokinetic profile.
Long half-life.

Source: Literature.^10–12

The growing interest due to the excellent results obtained with the insertion of biological products for the treatment of cancer, (whether they are monoclonal antibodies, therapeutic proteins, immunomodulators, and/or growth factors), as well as the breaking of patents for existing products and widely used, added to the interest on the part of the industries in the competition for the market, has been generating a great concern in the development of the biosimilars.^4,5,9

One of the major challenges facing regulatory agencies is to define standards that make it possible to compare the quality and purity of biological products in a similar way to low molecular weight drugs.^13,14 How to ensure that biosimilar medicine will have the same therapeutic effect and the ability to replace the biological reference product without causing damage or deficiencies in the treatment of cancer patients? With this problem in mind, this review article proposes to evaluate the safety in the interchangeability of biosimilar products approved for cancer treatment from a pharmaceutical perspective.

Methods

This review aims to highlight the likely risks and benefits in the interchangeability of biosimilar products for the treatment of cancer. To carry out this review, the following steps were followed: definition of the guiding question and research objectives; establishment of inclusion and exclusion criteria for selecting articles; literature search; analysis and categorization of studies, presentation, and discussion of results.

The period established for the articles was from 2004 to 2020, with 2005 being a milestone with approval in Europe for the production of biosimilar products. Data collection was performed through a bibliographic survey in the Sciencedirect, MEDLINE, and CAPLUS databases using the descriptors “Biosimilar”, “Oncology Therapy”, “Interchangeable drugs” and “Biological Products”.

The inclusion criteria adopted were complete articles that brought comparative clinical studies between biosimilar products and reference ones, articles that dealt with biosimilar products in oncology, and studies that brought clinical results only from biosimilar products without comparing them with reference ones. Regarding the adopted exclusion criteria, unavailable articles were excluded, which dealt with biosimilar products, but which did not refer to those applied in oncology, and articles that, although addressing the interchangeability of drugs, did not refer to biosimilar products.

Results and discussion

We identified 589 articles published in the databases in the first analysis. After reading and evaluating the articles, 453 articles were excluded because they did not meet the inclusion criteria, 28 articles were excluded because they were only available in summary and 61 articles were excluded because of repetition, with only 51 articles remaining for this review, also included 7 documents from the Food and Drug Administration (FDA), 2 documents from the European Medicines Agency (EMA) and 1 document from the World Health Organization (WHO). We emphasize that the journals Clinical Therapeutics and Transfusion and Apheresis Science are the journals that most published on the subject, representing 10.63% and 8.51% of publications respectively, followed by the European Journal of Cancer, Seminars in Oncology and The Lancet Hematology, both with 6.38% of publications as shown in Figure 1.

When evaluating the year of publications, it is noted that the year 2017 appears like the year with the most publications on the topic, representing 19.61% of the publications, followed by the years 2020, 2019, and 2018 with 15.69% and 2016 with 11.76% of publications (Figure 2).

The initiative in Europe

With the growing interest in biosimilars and concern for patient care, Europe created an initiative to include biosimilars in 2004, being the first biosimilar made available on the market in 2006. With the arrival of biosimilars in the European market, around 400 million patients were exposed to these drugs, contributing to various information regarding the use and safety of these drugs.¹⁵

The European Medicines Agency (EMA) determines that for a drug to be biosimilar it needs to demonstrate the same clinical benefits as the reference drug, based on the fact that all the main characteristics of the quality, safety, and efficacy profiles are the same. The effectiveness of comparability data must be proven through scientific studies and it is up to the EMA to authorize its use or not, and it is also responsible for monitoring the safety in its use after approval.¹⁵

To date, EMA has demonstrated the transformation in health care in the main therapeutic areas after the inclusion of biosimilar medicines in the European market, improving the safe access of patients and the sustainability of European health systems, with such results evidenced from the accumulation of real-world data.^15,16 To date, the European market has accumulated 68 drugs approved for sale, of which 23.53% were approved in 2018, while 8.82% of approved biosimilars were withdrawn from the market (Figure 3).

The situation of biosimilars in the United States (USA)

The Food and Drugs Administration (FDA) determines that biosimilar products must undergo more extensive clinical studies that allow verification in similarity with the reference. Also, the manufacturer must demonstrate that the biosimilar product has the same mechanism of action, route of administration, dosage form, and meets the appropriate manufacturing standards, highlighting as a requirement a comparison study of the biosimilar product and the reference when the immunogenicity.¹²

The FDA allows the manufacturer of the biosimilar medicine to extrapolate clinical data to support a determination of biosimilarity for each condition of use for which the license was requested provided it provides sufficient scientific justification, based on information as a target/recipient for each relevant activity of the product, the immunogenicity of the product in different populations and differences in toxicities expected in each use condition and patient population.¹²

A biosimilar product may not have all the indications of the reference product, which allows for several biosimilars for the same reference product with different matrices of indications approved by the FDA, this type of approval may confuse professionals working in oncology clinics, with the FDA recommends that the label of these products should also contain their indications.^11,12,17

The first biosimilar approved in the United States was in 2015, followed by 3 more biosimilars approved in 2016. The FDA reports that in 2,01,666 biosimilar products were registered and the Biotechnology Information Institute identified 797 biosimilars under development as of January 2017.¹² Figure 4 shows the profile of FDA approvals in the last 6 years, with an emphasis on 2019 with 35.71% of approvals.

Biosimilars in Brazil

In 2010, many Latin American countries began to develop biosimilar products, including Brazil, which has developed two routes of approval for comparable biological products that differ in the amount of data required for approval for the market. The first route is to include phase 1 pharmacokinetics and pharmacodynamics studies and phase 3 studies evaluated on a case-by-case basis, allowing for the extrapolation of indications. The second way of approval is through individual development, in which quality problems and clinical trial requirements are lower, but the extrapolation of indications is not allowed.¹⁸

To evaluate the biosimilars, the manufacturer must first perform a complete physical-chemical and biological characterization of the biosimilars through a direct comparison with the reference product, also evaluating based on the structures of the compounds.¹⁸

Comparability studies

Unlike chemically synthesized generic products, biosimilar products must be fully evaluated for quality, comparative clinical, and non-clinical studies with the reference product. The comparability studies of biosimilar products involve the comparability of the quality profiles of the biosimilar product and the reference one (Figure 5), this being the first approach.^19–22

Although the amino acid sequence of biosimilar products must be the same as that of the reference product, biosimilar products may have different profiles, with the need to classify structural differences as to their criticality, taking into account whether the differences will interfere with safety and effectiveness of the final product. Few products are currently available on the market, in which the vast majority are monoclonal antibodies. Due to difficulties in the production and control of biosimilars, also, there is no global consensus regarding the evaluation criteria for approval and authorization in the use of biosimilar medicines.^19–22

Glycosylation: A parameter for the evaluation of biosimilar products

With the insertion of biosimilars, much has been discussed to define parameters that structurally prove that biosimilars are similar to their reference products. Unlike small therapeutic molecules, biological products are large heterogeneous molecules prone to numerous modifications during their production, formulation, and storage. Therefore, changes in manufacturing conditions can result in large structural differences, making it impossible to create structurally identical copies.^17,23

These difficulties in the process of obtaining these products create problems for regulatory agencies to approve drugs that are interchangeable, leading to extensive scientific studies that compare and prove that there are no clinical differences between biosimilars, concerning safety, purity, and effectiveness for the reference product. Thus, it is necessary to carry out tests that prove structurally and chemically the biosimilar products associated with studies that prove the effectiveness compared to the reference product.^17,23

Glycosylation (Figure 6) is a natural process that occurs during the formation of a protein structure, this process will occur differently according to the protein that will be your final product, with different glycan sequences being generated that will modify the protein structure, this process is of great importance in the production of biosimilars because it allows the analysis of immunogenicity and clinical efficacy of therapeutic proteins. Most monoclonal antibodies of the IgG type have glycans linked to the N-glycosylation site, responsible for the effector functions mediated by the immune system, such as antibody-dependent cell-mediated cytotoxicity and complement of dependent cytotoxicity.^17,23,24

Changes in glycosylation patterns can affect the therapeutic efficacy of the drug, as well as lead to pharmacokinetic and pharmacodynamic changes, changes in the production and manufacturing process can substantially affect the glycosylation profile of the final product.^23,24

Li et al.²⁵ proposed in their study, as a method of comparing monoclonal antibody candidates to biosimilar, the mass spectrometry technique to assess the similarity of glycosylation of monoclonal antibodies. The results made it possible to identify variants among candidates for biosimilar and their respective reference products, leading the authors to conclude that mass analysis can play a crucial role in the characterization of variants of antibodies that are candidates for a biosimilar.

Concerns of the pharmaceutical class regarding the inclusion of biosimilars in the world market

The American Pharmacists Association (APhA) convened a conference with key stakeholders in biosimilar products, on November 30, 2016, in Washinton, DC. The main objective of the conference was to determine the problems and challenges related to the inclusion of biosimilar products in the market, defining the roles and responsibilities of pharmacists about these drugs, and identifying actions or activities of pharmacists to minimize barriers and challenges in the optimization of safety and use economic impact of biosimilar products.¹²

Organizations such as the FDA, Medicare, and Medicaid Service Centers (CMS), representatives of private companies, manufacturers, and health professionals attended this conference, highlighting interchangeability as the main problem in the inclusion of biosimilar medicines.¹² Interchangeability assesses the possibility of replacing a medication used by the patient with an equivalent one. Regulatory agencies have different interpretations that can cause confusion. The FDA (US) and the Canadian agency consider interchangeability as the possibility of the drug being replaced by the pharmacist, without the intervention of the prescribing physician, while EMA (Europe) and ANVISA (Brazil) define interchangeability as an exchange practice of a drug by another equivalent, in a given clinical context, under the initiative or with the consent of the prescriber.²⁶ When interchangeability is considered, the products are expected to produce the same clinical result in any patient in which it is administered, even if it has already been exposed to the reference product.^5,18

According to the Biologics Price Competition and Innovation Act (BPCIA) in 2009, pharmacists can replace interchangeable products with the reference product without the prescriber's authorization and pending state law requirements, noting that the first biological product interchangeable with a given reference product must have an exclusivity period of 1 year during which no other biosimilar to the reference product can be marketed. The interchangeability determination can make a product more competitive with the reference product, increasing patient access to the medicine they need at a reduced cost.^27,28

The BPCIA in the United States acts as a support to pharmacists, providing evidence that allows the replacement of biosimilars by pharmacists without intervention by the prescriber, similar to what happens with generic drugs. It is important to note that the biosimilar must present the same efficacy and safety profiles as the reference product and that the risks of switching from the reference product to the biosimilar must be less than the risk of using the reference product exclusively.²⁹

An important factor is that the biosimilar product may have the approval of other therapeutic indications if it presents safety, efficacy, and immunogenicity in its scientific studies, without having to present other clinical studies that prove each indication.^30,31 Extrapolation is a concept used for the development of biosimilars that allow regulatory approval for one or more therapeutic indications in addition to the one that was submitted to a clinical study, without specific studies having been carried out, but which are indications already approved by the biological reference product. The FDA essentially allows extrapolation of data for approved biological products, without requiring additional clinical studies.^11,32,33

ANVISA, on the other hand, predicts that if the product meets the requirements for licensing as a biosimilar, the potential exists for the biosimilar product to be licensed for one or more additional indications of use for which the reference product is already licensed. Extrapolation makes it possible to reduce the costs of developing new biological medicines, by eliminating the need to conduct new clinical studies for each of the indications previously approved for the reference product.^34,35

Pharmacoeconomics as an ally in the commercialization of biosimilars

The costs of antineoplastic therapy are increasing worldwide, along with the increase in new cases of cancer each year. One reason may be related to the cost of treatment for elderly cancer patients. Due to high health costs, many countries have enacted legislation authorizing the manufacture and distribution of small molecule generic drugs.^8,36

With the inclusion of biosimilar medicines, many countries are already showing savings in cancer treatment, an example of which is an estimate made in the European Union that forecasts savings of 1.6 billion with the inclusion of five biosimilar medicines, if they are successfully developed. Although biosimilar products can reduce costs, they will not be comparable to the cost savings generated by generic drugs, because biosimilar products require high manufacturing and development costs.^8,36

The introduction of biosimilar products will depend on several considerations, among which we can highlight the lack of understanding of the approval path, the pharmacovigilance and safety profiles, the education of health professionals and patients, as well as the issue of affordability and patent litigation, such variables can generate an increase in patient access, thus contributing to a change in treatment strategies.^8,36,37

Biosimilar drugs in oncology

Within the current health context, biological products have become a highly important factor in the treatment and control of cancer, considering the great challenges and benefits of the use of biosimilar medicines, the failure to recognize their importance as medicines in cancer treatment by patients and doctors can be interpreted as a failure in culture, science, politics, and medicine, in addition to contributing to their underutilization in clinical practice. Many authors also argue that biosimilars should not be developed as sub-optimal drugs, but their developers must be efficient in promoting cost minimization and competitive prices, without harming product quality, supply sustainability, or pharmacovigilance systems. Another important characteristic of this aspect of adherence to biosimilars in oncology is the prejudice about the real value of these drugs, which can make it even more difficult for patients to survive and widen inequalities, with oncologists understanding the concept of biosimilars extremely important.^38–41

With the loss of patent protection for biological medicines, the development of biosimilar products has become more and more common, causing a significant change in the pharmaceutical industry, such a scenario can be positively influenced by the emergence of new regulations and legislation that can potentially boost the use of biosimilars.^39,42 As a result, several biosimilar products are becoming available for a single reference drug, among the most studied biological drugs and disseminated through scientific articles in the development of biosimilars are Filgrastim, Rituximab, Trastuzumab, and Bevacizumab.^23,28

Comparative studies of filgrastim with its biosimilars

Cancer patients undergoing chemotherapy are at high risk of developing febrile neutropenia, which implies clinical decision-making regarding prophylaxis with granulocyte colony-stimulating factors (GCSF), with filgrastim being one of the main drugs used in patients with neutropenia.⁴³ Damaj et al.⁴⁴ evaluated the use of the biosimilar Zarzio Filgrastim in patients treated with chemotherapy for solid tumors, noting that doctors predominantly prescribe Zarzio to patients who are considered to be at high risk for neutropenia due to the chemotherapy regimen and/or a combination of risk factors due to the patient's characteristics.

As for the study of Aapro et al.⁴³ that evaluated the use of biosimilar filgrastim in the prophylaxis of chemotherapy-induced neutropenia, comparing elderly and non-elderly patients, showing that elderly patients have positive results in prophylaxis in hematological neoplasms than in solid (metastatic) tumors, showing the effectiveness of biosimilar filgrastim.

Danylesko et al.⁴⁵ evaluated the use of biosimilar Filgrastim (Tevagrastim) for mobilization and transplantation of allogeneic hematopoietic stem cells in patients with acute myeloid leukemia, compared with the reference filgrastim. The authors found that the effects of Tevagrastim are safe and efficient, obtaining results similar to the reference product, evidencing its similarity.

Another study with biosimilar filgrastim (Leucostim) was evaluated for its effectiveness compared to filgrastim in the mobilization of hematopoietic progenitor cells at a steady, through a multicenter study. The authors report that Leucostim has a similarity in effectiveness to the reference drug in the short term, but warns that more studies are needed to assess its long-term similarity.⁴⁶ Sivgin et al.⁴⁷ also compared the biosimilar filgrastim Leucostim with that of reference in the mobilization of stem cells in patients undergoing autologous transplantation of hematopoietic stem cells, highlighting the safety in their administration, emphasizing that the product would help in cost reduction, and further studies would be necessary to affirm these benefits in replacing the reference filgrastim.

Another study by Sivgin et al.⁴⁸ for assessing the efficacy and safety of Leucostim this time on cell mobilization in patients undergoing allogeneic hematopoietic stem cell transplantation, demonstrated that Leucostim has the potential to be used as an agent for stem cell mobilization in allogeneic transplantation, also reporting the need for prospective studies to ensure safety in the administration of Leucostim in patients with hematological cancer.

Tamura, Hashimoto, and Nishikawa⁴⁹ performed a prospective study after approval and commercialization of biosimilar filgrastim in Japanese patients, showing the absence of hypersensitivity reaction events or reduction in efficacy similar to the reference filgrastim, being effective in controlling neutropenia.

Gatzemeier et al.⁵⁰ evaluated the effectiveness of XM02, which is a biosimilar product that acts on granulocyte colony-stimulating factor, in patients with small-cell lung cancer with chemotherapy-induced neutropenia, in which the results obtained showed the benefit of XM02, highlighting the improvements not only in effectiveness but also in cost-benefit with the reference product.

Botteri, Krendyukov, and Curigliano⁵¹ compare the effects and safety of biosimilar products to filgrastim and pegfilgrastim through a meta-analysis, showing that there are no significant differences in clinical efficacy and safety between biosimilar drugs and those of reference in breast cancer patients who received chemotherapy.

A multicenter phase III study evaluated the effectiveness of biosimilar pegfilgrastim (Mecapegfilgrastim) in the prophylaxis of chemotherapy-induced neutropenia in patients with non-advanced small cell lung cancer. The authors demonstrate in their study that the long-acting mecapegfilgrastim compares favorably to the short-acting reference, with the advantage of a single dose per chemotherapy cycle.⁵² Brokx et al.⁵³ demonstrate the analytical similarity of the biosimilar pegfilgrastim with the reference, showing that the reported structural and functional data of the biosimilar pegfilgrastim are highly similar to the reference products.

Sun et al.⁵⁴ evidence the benefits in the economy with the introduction of biosimilar filgrastim in the European Union, demonstrating that despite the low values of biosimilar products, the lack of concrete studies is still a barrier in the prescription of these drugs, highlighting that economic differences are important in the reallocation resources, reducing health costs by up to 80%.⁵⁵ Studies show that filgrastim's biosimilar products are safe and effective in mobilizing hematopoietic stem cells when compared to the reference product, despite the results still being discussed in the scientific area regarding the similarity with the biological medicine, the differences in the manufacturing process, potential to cause immunogenicity, extrapolation, and interchangeability of biosimilar products.⁵⁵

Comparative studies of rituximab with its biosimilars

Rituximab is a monoclonal antibody widely used in the treatment of several tumors. In a double-blind, phase 3 study, Kim et al.⁵⁶ compared the efficacy, pharmacokinetics, and safety of CT-P10, which is biosimilar to rituximab, in patients with previously untreated advanced follicular lymphoma. The authors showed in their study that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to the reference rituximab, with a similar safety profile, and may represent a new therapeutic option for follicular lymphoma.

Ogura et al.⁵⁷ evaluated the efficacy, pharmacokinetics, and safety also of CT-P10 in comparison with the reference rituximab in the treatment of patients with previously untreated low tumor burden follicular lymphoma, verifying that the CT-P10 was equivalent to the reference rituximab, suggesting that the CT-P10 can be used as monotherapy in the treatment of patients with low tumor burden follicular lymphoma.With a double-blind and phase 3 study too, Jurczak et al.⁵⁸ evaluated the efficacy of biosimilar rituximab (GP2013) with that of reference in patients with advanced follicular lymphoma, showing how in the study of Kim et al.⁵⁶ that GP2013 represents a candidate in the treatment of follicular lymphoma and thereby increasing access to patients to treatment with reduced cost.

Comparative studies of trastuzumab with its biosimilars

Trastuzumab, like rituximab, is a monoclonal antibody that acts on cells that express the human epidermal growth factor 2 (HER2) receptor.⁵⁹ Melo et al.⁶⁰ analyzed the N-glycosylation profile of biosimilar candidates to trastuzumab using the liquid chromatography technique. The authors identified that the techniques used to identify the N-glycans of the trastuzumab biosimilars can be considered as routine methods for the characterization of the glycan profiles of these monoclonal antibodies.

Pivot et al.⁶¹ compared a candidate for biosimilar trastuzumab (SB3) and reference trastuzumab, through a randomized phase 1 pharmacokinetic study in healthy subjects, showing that the pharmacokinetics of SB3 is equivalent to the reference products and is well tolerated after single-dose administration. As a complement to this study Pivot et al.⁶² performed a phase 3 study comparing the SB3 and the reference trastuzumab in patients with HER2 positive initial breast cancer treated with neoadjuvant-adjuvant treatment. Despite performing a relatively short follow-up of patients, the results obtained in the study demonstrate a safety, immunogenicity, and survival similar to the reference trastuzumab, supporting the biosimilarity of SB3.

To assess the use of the SB3 biosimilar for 3 years, Pivot et al.⁶³ conducted a phase 3 study comparing SB3 with the reference trastuzumab in the neoadjuvant treatment for HER2 positive breast cancer, verifying a rare incidence in the development of cardiotoxicity by both treatments, showing only a higher event-free survival rate in the SB3 group compared to the group that received the reference trastuzumab. The authors believe that this difference may be related to a deviation in the activity of antibody-dependent cells in some batches of the reference trastuzumab.

Another phase 3 study was carried out by Alexeev et al.⁶⁴ where the main objective was to evaluate the efficacy, safety, and pharmacokinetics of the biosimilar BCD-022 in comparison with trastuzumab, at the end of this study the authors could conclude that these drugs are comparable, with no statistically significant variation in the parameters evaluated.

Pivot et al.⁶⁵ also conducted a phase 1 pharmacokinetic study on another trastuzumab biosimilar candidate (HD201) comparing with Herceptin, showing equivalence results in the pharmacokinetics between HD201 and the reference trastuzumab. The study will be followed by a new phase 3 study to assess the efficacy, safety, and immunogenicity of HD201 associated with docetaxel for the treatment of HER2 positive breast cancer.

Assessing the activity of another trastuzumab biosimilar candidate, Minckwitz et al.⁶⁶ compared ABP980 with reference trastuzumab in women with HER2 positive breast cancer, showing that the safety and efficacy results were equivalent to that of reference trastuzumab. The results of frequency, types, and severity of adverse events, including cardiac events, were not different from the results obtained with the reference trastuzumab, supporting the clinical similarity between ABP980 and trastuzumab.⁶⁷

Comparative studies of bevacizumab with its biosimilars

Bevacizumab is a humanized monoclonal antibody that acts on the vascular endothelial growth factor for the treatment of metastatic colorectal cancer, small cell lung cancer, metastatic kidney cancer, and glioblastoma. Peraza et al.⁶⁸ conducted a non-clinical study of bevacizumab biosimilar (PF-06439535), with an evaluation of peptide mapping, in vitro cell growth assays, and in vivo toxicity study in monkeys, showing the similarity between PF-06439535 with in vitro results with the reference Bevacizumab, while studies in rats and monkeys added limited value.

A study by Romera et al.⁶⁹ verified the similarity between bevacizumab biosimilar (BEVZ92) with the reference bevacizumab in combination with the FOLFOX or FOLFIRI protocols for first-line treatment for metastatic colorectal cancer. The results presented demonstrated equivalence between the BEVZ92 and the pharmacokinetically reference bevacizumab, with no differences in the efficacy, immunogenicity, and safety profiles in the first-line treatment of colorectal cancer associated with the FOLFOX or FOLFIRI protocols. The non-inferior efficacy and comparable tolerability of another bevacizumab biosimilar (BE1040V) could also be proven in phase III, multicenter, randomized, double-blind study for cases of metastatic colorectal cancer.⁷⁰

Conclusions

Biosimilar products in oncology are presented as a great opportunity to reduce costs in cancer treatment and increase competition in the market for biological products, enabling patients to access the treatment they need, thus enabling the change in the therapeutic scenario of cancer patients. Despite the benefits that biosimilar products are bringing, much is discussed about the similarity of biosimilars with their reference products.

Since the approval for the commercialization of biosimilar products in 2005 in Europe, there is still no global consensus on the best way to compare a biosimilar product with reference products. Studies indicate that only the comparative assessment of clinical efficacy and safety does not function as unique parameters for assessing equivalence, and studies that prove structural similarity are necessary, although it is impossible to obtain a biosimilar product extremely identical to the reference product, studies indicate that priority should be given to the structural characteristics that will maintain the efficiency and safety profiles of the reference product.

With such difficulty in obtaining a biosimilar product and for not obtaining a solid margin that guarantees 100% safety and interchangeability with the reference product, pharmaceutical professionals question whether, even with the reduction in cancer therapy costs, the interchangeability of these products with the reference ones would ensure quality in the treatment of cancer patients. Scientific studies, although proving the similarity of biosimilar products with reference products, do not guarantee that in the long term the results will be the same, nor have they evaluated the interchangeability of the products in patients who were already using the reference medicine.

Health professionals, especially pharmacists, have the responsibility to evaluate the use of biosimilar medicines after their commercialization through pharmacovigilance, assessing the risk-benefit, monitoring the effects of biosimilar products in the long term, being aware of the effects already caused by reference products to identify the long-term quality and safety of biosimilars.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Iago Dillion Lima Cavalcanti

References

Ferreira PMP and Pessoa C. Molecular biology of human epidermal receptors, signaling pathways and targeted therapy against cancers: new evidences and old challenges. Braz J Pharm Sci 2017; 53: 1–17.

Hirata

BKB

Oda

JMM

Guembarovski

, et al. Molecular markers for breast cancer: prediction on tumor behavior. Dis Markers 2014; 2014: 513158.

Wang

Targeted therapeutic options and future perspectives for HER2-positive breast cancer. Signal Transduct Target Ther 2019; 4: 34.

Scavone

Rafaniello

Berrino

, et al. Strengths, weaknesses and future challenges of biosimilars ’ development. An opinion on how to improve the knowledge and use of biosimilars in clinical practice. Pharmacol Res 2017; 126: 138–142.

Tkaczuk

KHR

Jacobs

IA.

Biosimilars in oncology: from development to clinical practice. Semin Oncol 2014; 41: S3–S12.

U.S. Food and Drug Administration - FDA. Biosimilar and Interchangeable Products. FDA, www.fda.gov/drugs/biosimilars/biosimilar-and-interchangeable-products#. :∼:text=A biosimilar is a biological,existing FDA-approved reference product. Published 2017. (accessed 16 April 2021).

Bui

Taylor

Developing clinical trials for biosimilars. Semin Oncol 2014; 41: S15–S25.

Henry

Taylor

Pharmacoeconomics of cancer therapies: considerations with the introduction of biosimilars. Semin Oncol 2014; 41: S13–S20.

Ahmed

Kaspar

Sharma

Biosimilars: impact of biologic product life cycle and European experience on the regulatory trajectory in the United States. Clin Ther 2012; 34: 400–419.

10.

Klein

Wang

Bedford

Subsequent entry biologics (biosimilars) in Canada: approaches to interchangeability and the extrapolation of indications and uses. Generics Biosimilars Initiat J 2014; 3: 150–154.

11.

USF. and DA. Biosimilars: questions and answers regarding implementation of the Biologic Price Competition and Innovation Act of 2009. Silver Spring, www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory%0AInformation/Guidances/UCM444661.pdf (2015, accessed 23 November 2019).

12.

Crespi-Lofton

Skelton

JB.

The growing role of biologics and biosimilars in the United States: perspectives from the APhA biologics and biosimilars stakeholder conference. J Am Pharm Assoc 2017; 57: e15–e27.

13.

Chirino

Mire-Sluis

Characterizing biological products and assessing comparability following manufacturing changes. Nat Biotechnol 2004; 22: 1383–1391.

14.

Dudzinski

Kesselheim

AS.

Scientific and legal viability of follow-on protein drugs. N Engl J Med 2008; 358: 843–849.

15.

EMA. Biosimilar medicines. Did you know?, www.medicinesforeurope.com/biosimilar-medicines/did-you-know/ (2019, accessed 23 November 2019).

16.

Santos

Lobo

JMS

Silva

AC.

Biosimilar medicines used for cancer therapy in Europe: a review. Drug Discov Today 2019; 24: 293–299.

17.

U.S. FDA. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. Silver Spring, www.fda.gov/ucm/groups/%0Afdagov-public/documents/document/ucm291128.pdf. (2015, accessed 23 November 2019).

18.

Bennett

Chen

Hermanson

, et al. Regulatory and clinical considerations for biosimilar oncology drugs. Lancet Oncol 2014; 15: e594–e605.

19.

Kwon

Joung

Park

, et al. Considerations of critical quality attributes in the analytical comparability assessment of biosimilar products. Biologicals 2017; 48: 101–108.

20.

EMA. Guideline on similar biological medicinal products, www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-rev1_en.pdf (2014, accessed 24 November 2019).

21.

WHO. Guidelines on evaluation of similar biotherapeutic products (SBPs). 2013. (977):51-89, www.who.int/biologicals/publications/trs/areas/biological_therapeutics/TRS_977_Annex_2.pdf?ua=1. (accessed 30 April 2021).

22.

Weise

From bioequivalence to biosimilars: how much do regulators dare?

Z Evid Fortbild Qual Gesundhwes 2019; 140: 58–62.

23.

Duivelshof

Jiskoot

Beck

, et al. Glycosylation of biosimilars: recent advances in analytical characterization and clinical implications. Anal Chim Acta 2019; 1089: 1–18.

24.

Higel

Seidl

Sörgel

, et al. N-glycosylation heterogeneity and the influence on structure, function and pharmacokinetics of monoclonal antibodies and Fc fusion proteins. Eur J Pharm Biopharm 2016; 100: 94–100.

25.

Yang

Zhou

, et al. Discovery and characterization of antibody variants using mass spectrometry-based comparative analysis for biosimilar candidates of monoclonal antibody drugs. J Chromatogr B 2016; 1025: 57–67.

26.

ANVISA AN de VS-. Intercambialidade entre produtos registrados pela via de desenvolvimento por comparabilidade (“biossimilares”) e o produto biológico comparador. ANVISA, www.gov.br/anvisa/pt-br (2017, accessed 17 April 2021).

27.

U.S. FDA. Food and drug administration. Considerations in demonstrating interchangeability with a reference product guidance for industry. Draft guidance. Silver Spring: Author. 2017.

28.

O’Brien

O’Mahony

Cooke

, et al. Cost minimization analysis of intravenous or subcutaneous trastuzumab treatment in patients with HER2-positive breast cancer in Ireland. Clin Breast Cancer 2019; 19: e440–e451.

29.

Cuellar

McBride

Medina

Pharmacist perspectives and considerations for implementation of therapeutic oncology biosimilars in practice. Am J Heal Pharm 2019; 76: 1725–1738.

30.

Markus

Liu

Ramchandani

, et al. Developing the totality of evidence for biosimilars: regulatory considerations and building confidence for the healthcare community. BioDrugs 2017; 31: 175–187.

31.

Lai

Noce

La. Key design considerations on comparative clinical efficacy studies for biosimilars: adalimumab as an example. Rheum Musculoskelet Dis 2016; 2: 1–13.

32.

U.S. Food and Drug Administration – FDA. Scientific considerations in demonstrating biosimilarity to a reference product, www.fda.gov/media/82647/download (2015, accessed 30 April 2021).

33.

U.S. Food and Drug Administration – FDA. BLA approval, www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/125553Orig1s000ltr.pdf (2015, accessed 30 April 2021).

34.

Anvisa

d V. Resolução da diretoria colegiada – RDC n° 55, de 16 de dezembro de 2010. Ministério da Saúde, http://bvsms.saude.gov.br/bvs/saudelegis/anvisa/2010/res0055_16_12_2010.html#. :∼:text=Dispõe sobre o registro de,o inciso IV do art (2010, accessed 30 April 2021).

35.

Weise

Kurki

Wolff-Holz

, et al. Biosimilars: the science of extrapolation. Blood 2014; 124: 3191–3196.

36.

Braud

Cross

Davenport-Ennis

, et al. NCCN biosimilars white paper: regulatory, scientific, and patient safety perspectives. J Natl Compr Cancer Netw 2011; 9: S1–S22.

37.

Whalen

Recognizing and addressing challenges to the adoption of trastuzumab biosimilars and HER2-targeted therapies. Am J Manag Care 2020; 26: S23–S31.

38.

Konstantinidou

Papaspiliou

Kokkotou

Current and future roles of biosimilars in oncology practice. Oncol Lett 2020; 19: 45–51.

39.

Saleem T, Qurashi H, Jamali M, et al. Biosimilars as a future, promising solution for financial toxicity: a review with emphasis on bevacizumab. Cureus 2020; 12: e9300.

40.

Trapani

Curigliano

How can biosimilars change the trajectory of breast cancer therapy? Expert review of anticancer therapy. Expert Rev Anticancer Ther 2020; 20: 325–328.

41.

Waller CF and Friganovic A. Biosimilars in oncology: key role of nurses in patient education. Futur Oncol 2020; 16: 1931–1939.

42.

Krendyukov A and Schiestl M. Biosimilars in oncology: a decade of experience with granulocyte colonystimulating factor and its implications for monoclonal antibodies. Crit Rev Oncol Hematol 2019; 23: 102785.

43.

Aapro

Bokemeyer

Ludwig

, et al. Chemotherapy-induced (febrile) neutropenia prophylaxis with biosimilar filgrastim in elderly versus non-elderly cancer patients : Patterns, outcomes, and determinants (MONITOR-GCSF study). J Geriatr Oncol 2017; 8: 86–95.

44.

Damaj

Benbrahim

Hacini

, et al. ZOHé: a prospective study of the use of biosimilar filgrastim zarzio in clinical practice in patients treated with chemotherapy for lymphoid malignancies. Clin Lymphoma, Myeloma Leuk 2017; 17: 362–369.

45.

Danylesko

Sareli

Bloom-Varda

, et al. Biology of blood and marrow transplantation biosimilar filgrastim (tevagrastim, XMO2) for allogeneic hematopoietic stem cell mobilization and transplantation in patients with acute myelogenous leukemia/myelodysplastic syndromes. Biol Blood Marrow Transplant 2016; 22: 277–283.

46.

Kayikçi

Tekgunduz

Kaya

, et al. Biosimilar filgrastim (leucostim®) have similar efficacy in steady-state hematopoietic progenitor cell mobilization compared to original filgrastim (neupogen®) and lenograstim (granocyte®): a retrospective multicenter study. Transfus Apher Sci 2017; 56: 832–835.

47.

Sivgin

Karakus

Kaynar

, et al. The comparison of filgrastim (neupogen Ò), biosimilar filgrastim (leucostim Ò) and lenograstim (granocyte Ò) as a first line peripheral blood stem cell mobilization strategy in autologous hematopoieitic stem cell tr. Transfus Apher Sci 2013; 48: 315–320.

48.

Sivgin

Karakus

Keklik

, et al. Evaluation of the efficacy and safety of original filgrastim (neupogen ®), biosimilar filgrastim (leucostim ®) and lenograstim (granocyte ®) in CD34 + peripheral hematopoietic stem cell mobilization procedures for a. Transfus Apher Sci 2016; 54: 410–415.

49.

Tamura

Hashimoto

Nishikawa

Clinical safety and efficacy of “filgrastim biosimilar 2” in Japanese patients in a post-marketing surveillance study. J Infect Chemother 2018; 24: 363–369.

50.

Gatzemeier

Ciuleanu

Dediu

, et al. XM02, the first biosimilar G-CSF, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with small cell. J Thorac Oncol 2009; 4: 736–740.

51.

Botteri

Krendyukov

Curigliano

Comparing granulocyte colony e stimulating factor filgrastim and pegfilgrastim to its biosimilars in terms of efficacy and safety : a Meta-analysis of randomised clinical trials in breast cancer patients. Eur J Cancer 2018; 89: 49–55.

52.

Zhou

Huang

Wang

, et al. A randomized multicenter phase III study of single administration of mecapeg filgrastim (HHPG-19K), a peg fi lgrastim biosimilar, for prophylaxis of Chemotherapy-Induced neutropenia in patients with advanced non e small-cell lung cancer (NSCLC). Clin Lung Cancer 2016; 17: 119–127.

53.

Brokx

Scrocchi

Shah

, et al. Biologicals a demonstration of analytical similarity comparing a proposed biosimilar PEG filgrastim and reference peg filgrastim. Biologicals 2017; 48: 28–38.

54.

Sun

Andayani

Altyar

, et al. Potential cost savings from chemotherapy-induced febrile neutropenia with biosimilar filgrastim and expanded access to targeted antineoplastic treatment across the European Union G5 countries : a simulation study. Clin Ther 2015; 37: 842–857.

55.

Korkmaz

Altuntas

Transfusion and apheresis science what is the role of biosimilar G-CSF agents in hematopoietic stem cell mobilization at present?

Transfus Apher Sci 2017; 56: 795–799.

56.

Kim

Buske

Ogura

, et al. Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 compared with rituximab in patients with previously untreated advanced-stage follicular lymphoma: a randomised, double-blind, parallel-group, non-inferiority phase 3 trial. Lancet Haematol 2017; 4: e362–e373.

57.

Ogura

Sancho

Cho

, et al. Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 in comparison with rituximab in patients with previously untreated low-tumour-burden follicular lymphoma: a randomised, double-blind, parallel-group, phase 3 trial. Lancet Haematol 2018; 5: e543–e553.

58.

Jurczak

Moreira

Kanakasetty

, et al. Rituximab biosimilar and reference rituximab in patients with previously untreated advanced follicular lymphoma (ASSIST-FL): primary results from a confirmatory phase 3, double-blind, randomised, controlled study. Lancet Haematol 2017; 4: e350–e361.

59.

Brain

Caillet

N de

, et al. HER2-targeted treatment for older patients with breast cancer: an expert position paper from the international society of geriatric oncology. J Geriatr Oncol 2019; 10: 1003–1013.

60.

Melo

Grassi

Ochoa

, et al. N-glycosylation profile analysis of trastuzumab biosimilar candidates by normal phase liquid chromatography and MALDI-TOF MS approaches. J Proteomics 2015; 127: 225–233.

61.

Pivot

Curtit

Lee

, et al. A randomized phase I pharmacokinetic study comparing biosimilar candidate SB3 and trastuzumab in healthy male subjects. Clin Ther 2016; 38: 1665–1673. DOI:doi:10.1016/j.clinthera.2016.06.002.

62.

Pivot

Bondarenko

Nowecki

, et al. A, Phase III study comparing SB3 (a proposed trastuzumab biosimilar) and trastuzumab reference product in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment: final safety, immunogenicity and survival results. Eur J Cancer 2018; 93: 19–27.

63.

Pivot

Pegram

Cortes

, et al. Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growth factor receptor 2 e positive breast cancer. Eur J Cancer 2019; 120: 1–9.

64.

Alexeev SM, Khorinko AV, Mukhametshina GZ, et al. Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-022 with reference trastuzumab. BMC Cancer 2020; 20: 783.

65.

Pivot

Deslypere

Park

, et al. A randomized phase I study comparing the pharmacokinetics of HD201, a trastuzumab biosimilar, with european union – sourced herceptin. Clin Ther 2018; 40: 396–405.

66.

Minckwitz

Von Colleoni

Kolberg

, et al. Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial. Lancet Oncol 2018; 19: 987–998.

67.

Kolberg

H-C

Colleoni

Demetriou

, et al. Cardiac safety of the trastuzumab biosimilar ABP 980 in women with HER2-Positive early breast cancer in the randomized, double-blind, active-controlled LILAC study. Drug Saf 2020; 43: 233–242.

68.

Peraza

Rule

Shiue

MHI

, et al. Nonclinical assessments of the potential biosimilar PF-06439535 and bevacizumab. Regul Toxicol Pharmacol 2018; 95: 236–243.

69.

Romera

Peredpaya

Shparyk

, et al. Bevacizumab biosimilar BEVZ92 versus reference bevacizumab in combination with FOLFOX or FOLFIRI as first-line treatment for metastatic colorectal cancer : a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol Hepatol 2018; 3: 845–855.

70.

Rezvani

Mortazavizadeh

Allahyari

, et al. Efficacy and safety of proposed bevacizumab biosimilar BE1040V in patients with metastatic colorectal cancer: a phase III, randomized, double-blind, noninferiority clinical trial. Clin Ther 2020; 42: 848–859.

71.

72.

Harston

How the U. S. Compares to Europe on biosimilar approvals and products in the pipeline, www.biosimilarsip.com/2019/05/07/how-the-u-s-compares-to-europe-on-biosimilar-approvals-and-products-in-the-pipeline-4/ (2019, accessed 24 November 2019).